Human epidermal growth factor receptor 2 (HER2) HER2 is overexpressed in approximately 25% of human breast cancers and is associated with a poorer clinical outcome as compared to breast cancers in which HER2 is not overexpressed. Much research has focused on developing therapies that specifically target HER2 and its signaling pathway. Examples of HER2-targeted therapies include trastuzumab, a monoclonal antibody that may be used alone or in combination with other therapeutic agents, and lapatinib, a small molecule tyrosine kinase inhibitor that is used in combination with other therapeutic agents.
Although the HER2-targeted therapy trastuzumab is widely used to treat patients who have HER2-overexpressing metastatic breast tumors, a significant number of patients fail to respond to trastuzumab treatment, and some patients who initially respond to the treatment regress within six months of the onset of treatment. It has been proposed that expression of an oncogenic isoform of HER2 called HER2Δ16 is involved in trastuzumab-refractory breast cancer (Mitra et al., Mol. Cancer Ther. 8(8):2152-2162 (2009)). HER2Δ16 is a splice variant of HER2 that lacks exon 16 and that, unlike HER2, is not expressed in normal (non-malignant) human tissues. While HER2 exists predominantly in monomeric form, HER2Δ16 in breast tumor cells exists as a stable, disulfide-linked homodimer. This HER2Δ16 homodimer activates multiple oncogenic signaling pathways, including the FAK, Src kinase, phosphatidylinositol 3-kinase/AKT, and mitogen-activated protein kinase pathways, in contrast to HER2, which only marginally activates each of these signaling pathways. HER2Δ16 expression is significantly associated with lymph node-positive breast cancer, a predictor of negative prognosis in breast cancer, and in vitro studies demonstrate that HER2Δ16 expression promotes cell proliferation, migration, and invasion of tumor cells. Additionally, breast tumor cells that overexpress HER2Δ16 exhibit trastuzumab resistance or even increased proliferation and invasion (Mitra et al., Mol. Cancer Ther. 8(8):2152-2162 (2009)).
Because HER2Δ16 expression is associated with enhanced cell tumorigenicity, activation of multiple oncogenic signaling pathways, and resistance to HER2-targeted trastuzumab treatment, patients expressing HER2Δ16 will require different and likely more aggressive therapeutic treatments if treatment is to be successful. Accordingly, there is a need in the art for compositions which will enable the development of assays for specifically detecting the presence of HER2Δ16 homodimers in samples of interest. The present invention satisfies this need and provides related advantages as well.